Brain mechanisms of reinforced placebo pill responses in chronic pain.

About This Grant

Abstract: We propose a proof-of-concept randomized and partially blinded trial to identify brain mechanisms for placebo pill responses when reinforced by cues and instructions. We will concentrate on chronic back pain patients (CBP) who have a large unmet need to properly control their daily pain, which exacts a huge toll on the individual and society and continues to contribute to the ongoing opioid crisis. Although mechanisms of placebo have been extensively studied in experimental settings, there is minimal knowledge of brain processes that control clinical placebo responses. Pain-relieving drug consumption is ubiquitous in chronic pain patients, even in those who pursue non-pharmacological treatments. The routines for drug consumption, however, remain open-ended and dependent on individuals' momentary decisions. Here, we test the concept of enhancing the placebo pill response by creating multiple feedback loops and reinforcement cues between daily back pain ratings and placebo pill consumption. We hypothesize that this enhanced placebo response is mediated through adaptations of the mesolimbic opioid-dependent circuitry. Prior literature and our preliminary results are consistent with this hypothesis. If we can identify brain circuitry for the enhanced placebo pill response and block this response by naloxone (blocking opioid receptors) through the same brain circuitry, then we would identify the causal mechanism for placebo pill responses. We also hypothesize that an enhanced placebo pill response will diminish experimental pain and improve motor abilities. Thus, we will study mechanisms for expectation-based training of the mind to improve subjective perception and objective bodily performance. 40 CBP (50% female, 50% Black) with back pain ≥ 4/10 (NRS score) are recruited and randomized (1:1) to 2 groups: 1) Reinforced placebo pill use (2 colors, up to 4 pills, positive reinforcement text messages), 2) Placebo pill use in the neutral condition (1 color pill, neutral texts). All participants will initially undergo a 1-week neutral single placebo pill consumption while rating back pain 3 times/day. The study will last 5 weeks. All participants will undergo brain scans and verbal interviews and fill out questionnaires at the start and end of the trial. We will assess motor abilities from smartphone mobility scores and collect the 30-second sit-stand test outcomes. Participants who complete the study undergo a 1-day randomized, blinded placebo/naloxone crossover study with 3 brain scans. We aim (1) to identify brain functional changes related to enhanced placebo, (2) to identify the effects of naloxone on brain activity, and explore sex, race, and socioeconomic influences on these outcomes. The study should be regarded as high-risk (a first effort to demonstrate mechanisms of placebo pill response) and high-impact (potentially can become part of routine chronic pain management).